The instant invention relates to the Flaviviridae family of viruses. The flavivirus genus includes about 70 members, 40 of which are associated with human illness. The majority of flaviviruses are arboviruses, transmitted to their avian and mammalian hosts, including man, by mosquitoes or ticks. Dengue fever virus (types 1-4), yellow fever virus, Japanese encephalitis virus, tick-borne encephalitis virus and West Nile virus are causative agents of significant morbidity and mortality in human populations. Several flaviviruses, including louping ill that causes neurological disease in sheep, West Nile that causes encephalitis in horse, and Japanese encephalitis that also causes encephalitis in horses as well as stillbirth in domestic pigs, are important veterinary pathogens.
Flavivirus genomes consist of a single linear, single-stranded + sense RNA. The + strand is capable of infecting appropriate host cells. The total genome can range from 10 to 11 kbs. There is no 3′ polyadenylation. The 5′ end has a methylated cap.
Flavivirus genomes do not contain internal ribosomal entry sites (IRES) that provide a site of translation initiation for host ribosomes. Instead flavivirus employs ribosomal scanning to commence protein synthesis.
Flavivirus virions are spheres, 40-65 nm in diameter. Under the lipid envelope is an icosahedral capsid coat approximately 25-30 nm in diameter.
Generally, flaviviruses are transmitted by arthropods, for example, mosquitoes and ticks. Flaviviruses reproduce in their vector organism and are passed from one host to the next.
The yellow fever virus is capable of causing large epidemics. The yellow fever virus is transmitted in monkey and human hosts and in mosquitoes. In the first cycle, the virus is transmitted by Aedes africanus and other Aedes mosquitoes (in Africa) or by Hemogogus mosquitoes (in the Americas); monkeys serve as the reservoir, and generally, humans infected are those who enter deep forests and jungles. In the second cycle, the domestic mosquito, Aedes aegypti, which lives in close relationship with humans, may transmit the virus directly to humans, the sole host in the cycle.
The tick-borne encephalitis virus is transmitted by ticks of the genus Ixodes in temperate regions of Russia and Europe. The virus can only affect humans in areas where the ticks exist.
Flaviviruses cause other encephalitic diseases, such as, Murray Valley encephalitis, Rocio and Powassan encephalitis, and as more recently observed in North America, West Nile fever.
Dengue fever is an acute infectious disease characterized by biphasic fever, headache, pain in various parts of the body, prostration, rash, lymphadenopathy and leucopenia (Holstead, S B, 1980, Immunological parameters of togavirus disease syndromes, p. 107-173, in R W Schlesinger (ed.) The Togaviruses, Academic Press, Inc., NY; Sabin, A B, 1959, Dengue, p. 361-373, in T Rivers and F Horsfall (eds.), Viral and Rickettsial Infections of Man, JB Lippincott Co., Philadelphia).
Dengue is mosquito-borne and caused by four serologically related viruses known as dengue virus type 1 to type 4 (dengue-1 to dengue-4). Infection with one dengue serotype provides lifelong immunity to that subtype, but no cross-protective immunity to the other serotypes. Thus, persons living in an area of endemic dengue can be infected with three, and possibly four, dengue serotypes during their lifetime. Illness ranges from unapparent infection to dengue fever or, in severe cases, potentially fatal dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS).
Dengue hemorrhagic fever (DHF) is a severe febrile disease characterized by abnormalities of hemostasis and increased vascular permeability, which in some instances results in a hypovolemic shock syndrome, dengue shock syndrome (DSS) (World Health Organization: 1975. Technical Guides for Diagnosis, Treatment, Surveillance, Prevention and Control of Dengue Hemorrhagic Fever. World Health Organization. Geneva). The mechanism of DHF/DSS may vary in different cases. The major factors contributing to DHF/DSS may include viral virulence, patient health status and secondary infection of different serotype dengue virus.
Considering the urgent need for flavivirus vaccines, a novel alternative approach is needed. Theoretically, live attenuated vaccines elicit the most effective, long-term, virus-specific immunity, and inactivated virus vaccines, including recombinant subunit vaccines, provide the highest level of safety. The ideal vaccine would be the one that can produce the efficacy of a live vaccine and the safety of subunit vaccine. That goal was met in the development of the pseudoinfectious virus-like particle (PVLP) flavivirus vaccines described herein.